Expression cloning and signaling properties of the rat glucagon receptor

Jelinek, Laura; Lok, Si; Rosenberg, Gary B.; Smith, R. Percy; Grant, Francis James; Biggs, S; Bensch, P.; Kuijper, Joseph L.; Sheppard, Paul O.; Sprecher, Cindy A.; Et, Angelakos

doi:10.1126/science.8384375

Cited by 399 publications

(236 citation statements)

References 20 publications

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“…Jelinek et al (1993) recently described the cloning, expression and signalling properties of the rat glucagon receptor. The cloned receptor was reported to increase intracellular cyclic AMP following the binding of glucagon.…”

Section: Possible Loci In the Signalling Transduction Pathways Where mentioning

confidence: 99%

Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

Bygrave

Benedetti

1993

Biochemical Journal

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Section: Possible Loci In the Signalling Transduction Pathways Where mentioning

confidence: 99%

Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

Bygrave

Benedetti

1993

Biochemical Journal

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“…Clones were selected in the presence of 200 g͞ml G418 (GIBCO͞BRL) and expanded. Clone H22 was selected for stable expression of GR based on specific glucagon binding and glucagon-induced signaling assays (1,6,7). Transient transfection of HEK 293 cells was performed on 80% confluent monolayers in 60-mm plates by using Lipofectamine.…”

Section: Methodsmentioning

confidence: 99%

“…G lucagon exerts its regulatory effects on hepatic glucose production by binding to the glucagon receptor (GR) (1). GR belongs to the superfamily of heptahelical transmembrane G protein-coupled receptors (GPCRs), which is divided into subfamilies based on amino acid sequence comparison.…”

mentioning

confidence: 99%

Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase

Jiang

Cypess

Muse

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We prepared a stable cell line expressing the glucagon receptor to characterize the effect of Gs-coupled receptor stimulation on extracellular signal-regulated protein kinase 1͞2 (ERK1͞2) activity. Glucagon treatment of the cell line caused a dose-dependent increase in cAMP concentration, activation of cAMP-dependent protein kinase (PKA), and transient release of intracellular calcium. Glucagon treatment also caused rapid dose-dependent phosphorylation and activation of mitogen-activated protein kinase kinase͞ ERK kinase (MEK1͞2) and ERK1͞2. Inhibition of either PKA or MEK1͞2 blocked ERK1͞2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Ras, Rap1, and Raf, was observed in response to glucagon treatment. In addition, chelation of intracellular calcium reduced glucagon-mediated ERK1͞2 activation. In transient transfection experiments, glucagon receptor mutants that bound glucagon but failed to increase intracellular cAMP and calcium concentrations showed no glucagon-stimulated ERK1͞2 phosphorylation. We conclude that glucagon-induced MEK1͞2 and ERK1͞2 activation is mediated by PKA and that an increase in intracellular calcium concentration is required for maximal ERK activation.G lucagon exerts its regulatory effects on hepatic glucose production by binding to the glucagon receptor (GR) (1). GR belongs to the superfamily of heptahelical transmembrane G protein-coupled receptors (GPCRs), which is divided into subfamilies based on amino acid sequence comparison. Most GPCRs fall into family A, the opsin͞adrenergic receptor subfamily. GR is in family B, which shares few amino acid sequence similarities with the other GPCRs. Nevertheless, family B receptors generally couple to the same heterotrimeric G protein classes and activate the same sets of downstream effectors and signaling networks as the family A receptors.One set of downstream effectors is the mitogen-activated protein (MAP) kinases, which include extracellular signalregulated protein kinase 1͞2 (ERK1͞2), p38, and c-Jun Nterminal kinase͞stress-activated protein kinase. These cytoplasmic serine͞threonine protein kinases are critical points of convergence for cellular signal transduction pathways leading to cellular differentiation, proliferation, and transformation (2). ERK1͞2 MAP kinases originally were shown to be activated by receptor tyrosine kinases that relied on a cascade of proteinprotein interactions and phosphorylations proceeding through Ras, Raf, and MAP kinase kinase͞ERK kinase (MEK1͞2) (3). It has since been shown that each of the four families of heterotrimeric G proteins (G s , G i , G q , and G 12 ) activates, or sometimes inhibits, MAP kinase activity (4, 5). Although much attention has been focused on regulation of MAP kinases by family A GPCRs, much less is known about how family B receptors regulate MAP kinase activity.We prepared a clonal cell line from human embryonic kidney (HEK) 293 cells that stably expressed a synthetic gene for the rat GR. Glucagon treatment of the cells ...

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“…The wide range of actions of glucagon is correlated to the equally wide tissue distribution of its specific receptor (Gcgr), which has been cloned from rat (7), human (8), and mouse (9). Sequence homology analysis indicates that the Gcgr is a member of the class B family of heptahelical GTP-binding protein (G protein) coupled receptors, which includes those for the related peptides GLP-1 and glucose-dependent insulinotropic polypeptide (10).…”

mentioning

confidence: 99%

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Gelling

Dichmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

511

613

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Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic ␣ cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr ؊/؊ ). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr ؊/؊ mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to ␣ cell, and to a lesser extent, ␦ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3-to 10-fold increase in circulating GLP-1 amide. Gcgr ؊/؊ mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and ␣ and ␦ cell numbers. Furthermore, the lean phenotype of Gcgr ؊/؊ mice suggests glucagon action may be involved in the regulation of whole body composition.

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Expression cloning and signaling properties of the rat glucagon receptor

Cited by 399 publications

References 20 publications

Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

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